A research team supported in part by MDA has shown that an abnormal reaction of the immune system against a protein called LRP4 can be added to the known causes of myasthenia gravis (MG), a disorder involving fluctuating weakness and fatigue because of impaired nerve-to-muscle communication. MG is an autoimmune disease, meaning it's caused by abnormal activity of the body's immune system against its own tissues.

The findings will allow more patients to get a specific diagnosis and may lead to improvements in treatment.

When laboratory mice were immunized against their own LRP4 protein molecules, they developed the typical muscle weakness and fatigue associated with human MG, as well as the impaired nerve-to-muscle signaling and abnormally structured neuromuscular junctions associated with this disorder. Neuromuscular junctions are places where muscle fibers receive signals from nerve fibers.

Mice that received anti-LRP4 antibodies generated in rabbits developed similar symptoms.

"Our identification of anti-LRP4 antibodies indicates that MG is likely to be a complex disease entity, which can be classified into different subtypes with different etiologies [causes]," the study's authors write.

MDA grantee Lin Mei, director of the Medical College of Georgia (MCG) Institute of Molecular Medicine and Genetics, led the research team, and MCG postdoctoral fellow Chengyong Shen was first author on the study.

Three causes for MG now recognized

Other known causes of MG include antibodies — proteins produced by the immune system — against the acetylcholine receptor protein as well as antibodies against the MuSK protein. Both these proteins play essential roles in nerve-to-muscle signaling at neuromuscular junctions.

Medications that improve nerve-to-muscle signal transmission or suppress the immune system are common treatments for MG.

It's been estimated that anti-acetylcholine receptor antibodies account for about 80 percent of cases of MG and that anti-MuSK antibodies account for an additional 8 to 14 percent. The cause of the disorder in the remaining 6 to 12 percent has remained unexplained, but it is now clear that LRP4 antibodies account for it in at least some of these patients.

Previous studies have shown that some people with MG without antibodies to an acetylcholine receptor protein or MuSK showed antibodies against the LPR4 protein. However, until now, it has not been clear that these antibodies were the cause of their disorder.

Implications of the LRP4 findings

The new findings have implications for understanding both the LRP4 protein (whose full name is lipoprotein receptor-related protein 4) and the MG disease process.

LRP4 was previously recognized as playing a role in the formation of neuromuscular junctions. The recent work shows the protein is also important in maintaining these junctions later in life.

Commenting on the benefits for those with MG, Mei said, "We hope our findings will enable more patients to receive a definitive diagnosis of myasthenia gravis and, ultimately, will lead to more targeted therapies, rather than the broad suppression of the immune system commonly used today."

The investigators say that future studies of large groups of MG patients should help clarify the percentage of people with MG who have LRP4-related disease.